Reactions Hantzsch dihydropyridine

Two- and three-component Hantzsch reactions using C-glycosylated reagents have been reported as an alternate method for conducting asymmetric syntheses of 1,4-dihydropyridines." ° Reaction of 109, 110 and 97 generate 111 with Ri = sugar. Alternatively, 112 and 113 produce 111 with Ri = sugar. While the yields were acceptable (60-90%), the diastereomeric ratio varied from 30-60%. 

Pyridines are traditionally prepared using the Hantzsch reaction, a condensation between 2 mol of a 6-ketoester, 1 mol of an aldehyde and 1 mol of ammonia. The product of this reaction is a 1,4-dihydropyridine which can be further oxidized to the corresponding pyridine compound (as 155 in Scheme 54). A first report described the Hantzsch reaction carried out under microwave irradiation on Bentonite clay and ammonium nitrate as ammonia... 

Hantzsch cyclization of 214 to dihydropyridines 216 can be accomplished by treating 215 with 214 in the presence of NaOEt (Equation 29). Under these conditions, dihydropyridines 216 are obtained in 41-64% yields. A three-component Hantzsch reaction using 214, aldehyde 217, and /3-keto ester 218 under similar conditions affords 219 in 51% yield (Equation 30) <2005JOC5331>. 

The Hantzsch reaction that allows the synthesis of pyridine derivatives, is a condensation involving two equivalents of a yS-ketoester or a yS-ketoamide, one equivalent of an aldehyde and ammonia. The Hantzsch reaction was used by Patel et al. for the synthesis of a 300 member dihydropyridine library (Scheme 3.27) [287]. 

Scheme 3.27 Hantzsch reaction for the synthesis of dihydropyridine derivatives (189) [287],...

Debache A, Ghalem W, Boulcina R, Belfaitah A, Rhouati S, Carboni B (2009) An efficient one-step synthesis of 1,4-dihydropyridines via a triphenylphosphine-catalyzed three-component Hantzsch reaction under mild conditions. Tetrahedron Lett 50 5248-5250... 

There are some methods that are specific to HCHO. For example, the Hantzsch reaction of HCHO, collected with a diffusion scrubber, with ammonium acetate, acetic acid, and acetylacetone to form diacetyldihydrolutidine, which is measured using its fluorescence at 470 nm, has been applied to air measurements (Dasgupta et al., 1988, 1990 Kleindienst et al., 1988a,b Lawson et al., 1990 Khare et al., 1997). Reaction with 1,3-cyclohexanedione and ammonium acetate to form a dihydropyridine derivative that is measured by fluorescence has been used in conjunction with a diffusion scrubber (Fan and Dasgupta, 1994). Enzymatic methods have been used in which formaldehyde dehydrogenase catalyzes the oxidation of HCHO to HCOOH in the presence of -nicotinamide adenine dinucleotide, NAD+, which is reduced to NADH. The latter is measured by fluorescence at 450 nm (Lazrus et al., 1988 Ho and Richards, 1990). 

The utility of some of these products for side-chain modification has also been demonstrated. For example, 4-chloro-3-formylpyridine undergoes the Hantzsch reaction to give a 4-(3-chloropyridine)-l,4-dihydropyridine derivative (88%). (4-Chloro-3-pyridyl)diphenylmethanol affords aza-analogues (65-70%) of the antimycotic agent chlortrimazol by reaction with thionyl chloride and imidazole derivatives (88JHC81). 

For the preparation of 4-aryI-l,4-dihydropyridine derivatives, there are two general approaches, shown in the Scheme 1, which involve variants of the Hantzsch reaction [ref. 14,15],... 

The classical Hantzsch reaction, the formation of dihydropyridines from an aldehyde, a 5-keto ester and an amine, was first described in 18826. In the 1940s, the interest for this substance class increased due to its pharmacological activity, for example, 4-aryl-1,4-dihydropyrdines form an important class of calcium channel antagonists such as Nifedipin. 

Although the exact reaction mechanism for this three-component condensation reaction was not confirmed in [193, 194], the hypothesized mechanism is likely to involve the initial base-catalyzed formation of the Michael adduct, and its subsequent reaction with the aminopyrazole component to furnish the tricyclic intermediate (Scheme 3.63). Elimination of water from this intermediate leads to the formation of the classic Hantzsch-type dihydropyridine... 

Another modification of the Hantzsch reaction for synthesis of 1,4-dihydropyridines starts from 2-benzylidene-l,3-diones and alkyl aminocrotonates87 or a / -aminopenten-a-one88 (equation 62). The synthesis is simple and generally applicable89 though the yields are not very high and side products are observed. 

The first important MCR was developed by Strecker in 1850 (Scheme 1) [20]. In this reaction ammonia, an aldehyde and hydrogen cyanide combine to form a-cyano amines 1, which upon hydrolysis form a-amino acids 2. Also, heterocyclic compounds were obtained using MCRs. An example of this is the Hantzsch reaction, discovered in 1882 [21]. This reaction is a condensation of an aldehyde with two equivalents of a (3-ketoester in the presence of ammonia resulting in the formation of dihydropyridines 3. A comparable reaction is the Biginelli reaction, founded in 1893 ([22] and see for review [23]). This reaction is a 3-component reaction (3CR) between an aldehyde, a (3-ketoester and urea to afford dihydropyrimidines 4. 

Several papers have been published that highlight the use of the Hantzsch reaction for the synthesis of compounds that exhibit ion channel modulating activity. The majority of protocols invoke dihydropyridine synthesis as outlined in Schemes 13 and 14. 

Saini A, Kumar S, Sandhu JS (2008) Hantzsch reaction recent advances in Hantzsch 1, 4-dihydropyridines. J Sci Ind Res 67 95-111... 

Formally, one can also propose the formation of the 2,5-dihydro isomer, but even if this isomer does form during the reaction, it is easily transformed to the thermodynamically more stable 1,2-dihydro compound. This reaction is nearly identical to the classical Hantzsch s synthesis of dihydropyridines, with only the molar ratio of starting materials being changed. However, in contrast to the widely investigated Hantzsch reaction, there are few examples in the literature, and it needs detailed study. 

Three different pyridine syntheses starting from polymer-bound enones have been reported. The first synthesis starts from 2-alkylidene- or 2-arylidene-B-ketoesters immobilized on Wang or Sasrin resin (Fig. 6.21). These substrates reacted with enaminones in a Hantzsch reaction to 1,4-dihydropyridines which could be oxidized to the corresponding pyridines with ceric ammonium nitrate (CAN). Cleavage was performed with TFA/DCM. Sixteen compounds were synthesized, with HPLC purities of between 70% and 99%. 

In 1882, Hantzsch achieved the synthesis of symmetrically substituted dihydropyridines (DHPs) by reacting ammonia, aldehydes, and two equivalents of yS-ketoest-ers [27]. Since then, interest in these types of compound has grown, because of their pharmacological activity [28]. The Hantzsch reaction has successfully been used for synthesis of a wide range of DHPs and is still a popular tool for the construction of members of this class of heterocycles [29]. The classical multicomponent synthesis may require extended reaction times and yields can be low if sterically hindered aldehydes are used [30]. 

Davis and coworkers have used an intramolecular asymmetric Michael addition to an optically pure a,(3-unsaturated sulfoxide as part of the synthesis of the dihydropyridine sulfone (132), a potent antihypertensive agent [108], The Hantzsch reaction (treatment with 3-aminocrotonate (130) in MeOH under reflux) of the a-acyl-a,P-unsaturated sulfoxide (129) gave the product (131) as a single diastereoisomer in 48% yield, resulting from an asymmetric Michael addition followed by dehydrative cyclization. The sulfoxide was then oxidized to the corresponding sulfone (132) (Scheme 5.44). 

Nature makes use of NADH (reduced nicotinamide adenine dinucleotide) as a cofactor for enantioselective biochemical hydrogenations, which are typical hydride-transfer reactions. Dihydropyridines and benzimidazolines derivatives are active hydride donors due to the presence of the nitrogen atom and the ability of the molecule to undergo aromatisation. Organocatalytic enantioselective reductions carried out using hydride donors has been studied, and effective reductions have been achieved with imidazoli-dinone organocatalysts, both with a,p unsaturated aldehydes and ketones. Generally, a stoichiometric quantity of reductant (Hantzsch ester 4) is required for these transformations (Scheme 18.5). 

Hantzsch s dihydropyridine derivatives are the analogs of NADH coenzymes and constitute the skeleton of many drug molecules such as nifedepine, amlodepine, besylate, and so on. A mild protocol for the synthesis of 1,4-dihydropyridine derivatives by the condensation of aldehydes, 1,3-dicarbonyl compounds, and ammonium acetate in the presence of SSA under solvent-free conditions was developed by Datta and Pasha et al. (2011) (Scheme 5.4). This method has several distinct advantages such as an environmentally benign nature, high yield, short reaction time, and so on. 

H. Banitaba, S. D. KhalUi, J. Mol. Catal. A Chem. 2011, 335, 46-50. Cellulose sulfuric acid catalyzed multicomponent reaction for efficient synthesis of 1,4-dihydropyridines via unsymmetrical Hantzsch reaction in aqueous media. 

K. Arundhathi, K. Sudhakar, B. S. Sastry, J. S. Yadav, Synth. Commun. 2009, 39, 2843—2851. Ced YH O-catalyzed one-pot synthesis of Hantzsch 1,4-dihydropyridines at room temperature, (f) E. Mosaddegh, A. Hassankhani, Bull. Chem. Soc. Ethiop. 2012, 26, 461—465. One-pot synthesis of polyhydropyridine derivatives via Hantzsch four component condensation in water medium use of a recyclable Lewis acid CelSO ) catalyst, (g) M. Hong, C. Cai, W. B. Yi, J. Eluor. Chem. 2010, 131, 111-114. Hafnium (IV) bis(perfluorooctanesulfonyl)imide complex catalyzed synthesis of polyhydro-quinoline derivatives via unsymmetrical Hantzsch reaction in fluorous medium. 

G. V. M. Sharma, K. L. Reddy, P. S. Lakshmi, P. R. Krishna, Synthesis 2006, 55-58. In situ" generated HCT-an efficient catalyst for solvent-free Hantzsch reaction at room temperature synthesis of new dihydropyridine glycoconjugates. 

The synthesis of various substituted 1,4-dihydropyridines has been achieved by the reaction of aldehydes, ethyl/methyl acetoacetates, and ammoninm acetate in water using a phase-transfer catalyst (tetrabutyl ammoninm bromide) nnder micro-wave irradiation (Scheme 8.13) [13]. Compared to the classical Hantzsch reaction conditions, this new method consistently has the advantage of good yields and short reaction times. 

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